Current Members
Methodology Development for Oligosaccharide Synthesis
Concept I: Strain-Release Driven Glycosylation
Achieving chemical glycosylation with controlled selectivity is a pivotal pursuit in the glycoscience. We have exploited the strained 3-member ring structure of CCBz to design a new generation of glycosyl donors amenable to highly efficient, low-cost, easy to conduct and environmentally friendly chemical glycosylation reactions with excellent stereoselectivity. The new reactions applies to a wide range of acceptors and enables facile access to challenging oligosaccharide structures. For details of the reactions, See: Nat. Comm. 2023,14, 1; Chem. Sci. 2024, 15, 3711; CCS Chem., 2023, 5, 2910.
Concept II: Acceptor-Controlled Glycosylation
Hydrogen bond mediated dual-directing glycosylation
Palladium mediated inner/outer sphere glycosylation
Stereoselective chemical glycosylation reactions were typically achieved with design of glycosyl donors. We are among the first researchers who demonstrated that the reactivity of glycosyl acceptors can also be exploited for achieving controlled stereoselectivity. The new concept and corresponding methodologies have been successfully applied to efficiently construct different types of glycosidic bonds, enabling chemical access to a variety of oligosaccharides and glycoconjugates. Our contribution was summarized in the following review papers and book chapters: Acc. Chem. Res. 2018, 51, 628; Nat. Commun. 2014, 5, 5051; Angew. Chem. Int. Ed., 2015, 54, 604; etc.
Concept III: Protection-less/free Glycosylation
Traditional regio- and stereo selective chemical glycosylation reactions for synthesis of complex oligosaccharides rely heavily on installation and repetitive removal of multiple orthogonal protection groups on the glycosyl donors and acceptors. The boron-mediated protection-less/free glycosylation we developed, minimizing the laborious orthogonal protection/deprotection steps, significantly shortens the synthetic route for preparation of oligosaccharides. With great advantages and flexibility (Figure 3), our synthetic protocols can be more elegantly streamlined for both linear oligosaccharides and branching N-glycans. For published works, see: Nat. Commun. 2017, 8, 1146; etc.
Glycoprotein Synthesis
Concept I: Dual Native Chemical Ligation (dNCL) for glycoprotein synthesis
Asp-based dual native chemical ligation and glycoprotein synthesis
Lys-based dual native chemical ligation and di-ubiquitin synthesis
We developed a practical approach towards synthesis of N-glycopeptide and N-glycoprotein synthesis using an auxiliary-mediated dual native chemical ligation (dNCL). The published work (Angew. Chem. Int. Ed., 2016, 55, 10363) was highlighted by X-MOL. And, in collaboration with Prof Liu Chuanfa’s group, we designed and synthesized the agent 4-mercaptolysine to mediate dual chemical ligation at both α- and ε-amines of lysine residue via a 6-membered ring transition state. It has become a general strategy for preparation of branched peptides. For published results, see: Bioorg. Med. Chem. Lett., 2009, 19, 6268; J. Am. Chem. Soc., 2009, 131, 13592. This work was highlighted twice by Chemical & Engineering News (C&EN, Sept. 21, 2009; and Nov. 16, 2009). This method was applied to the synthesis of K48-linked di-ubiquitin (Chem. Commun., 2010, 46, 7199) and highlighted by Chemical & Engineering News (C&EN, Oct. 11, 2010, PP36-37). It was also selected for Chemical Year in Review (C&EN, Dec. 20, 2010, PP13-17). The dual Native Chemical Ligation (dNCL) concept and methodologies enable quick assembly of tagged peptides and post-translationally modified proteins.
Glycobiology & Bioengineering
Concept: Exploring & Exploiting Lectin-Glycan Interactions
“Turn off/turn on” biosensor
Cell secretion biosensor
Carbohydrate-lectin interactions are fundamentally important in various biological processes and play key roles in cancers, immune diseases, infectious diseases, etc. We have been exploring and exploiting carbohydrate-lectin interactions at the cell surface with chemical approaches. We developed a novel “turn-off/turn-on” biosensor system to quantify any specific carbohydrate-lectin interactions. (J. Am. Chem. Soc., 2012, 134, 15229; Chem. Sci., 2017, 8, 3980.) and a cell secretion biosensor which provides real-time and non-invasive measurements from living cells with high sensitivity, high temporal resolution, high throughput and ease of use (Angew. Chem. Int. Ed., 2009, 48, 2723; Chem. Eur. J., 2010, 16, 4533; Chem. Soc. Rev., 2010, 39, 2925.). Our results exemplifies how a interdisciplinary combination of glycoscience and nanotechnology creates new opportunities for biology. Our sugar-based sensors can be applied to screen the side effects of drugs and drug candidates on central nervous system in developing new drugs.
Natural Product Synthesis
Concept: Facile Access to Natural Products from Glycan Scaffold
Employing sugar synthons in organic synthesis often provides unexpected conciseness and new possibilities. We are strongly interested in economic synthesis of biologically unique natural products and drugs, starting from sugars. For published results, see: Angew. Chem. Int. Ed., 2011, 50, 12054; Angew. Chem. Int. Ed., 2013, 52, 5134; Chem. Eur. J., 2014, 20, 405; Angew. Chem. Int. Ed., 2014, 53, 10742; Chem. Sci. 2017, 8, 6656; etc.
Synthesis and Biological Invesitigation of Peptidoglycan Analogues
Concept I: PGO Synthesis from Chitosan
Peptidoglycans are idiosyncratically bacterial structures ubiquitously present in the bacterial cell wall with conserved pathway of biosynthesis, widely deemed as potential target for development of wide-spectrum antibiotics. We developed the first top-down approach to synthesize biohybrid peptidoglycan oligomers (PGOs) in a highly practical and efficient manner, starting with the lost-cost biopolymer chitosan derived from shrimp shell and produced in large quantities. We confirmed the incorporation of PGO into the cell walls of multiple strains of wild-type bacteria. We have demonstrated that PGOs can be a powerful tool to study bacterial cell wall biogenesis and antimicrobial therapeutics. Results were published at Chem. Sci., 2020, 11, 3171.
Concept II: Facile Synthesis of GlcNAc-1,6-anhydro-MurNAc Analogue of PGO
Inspired by the natural 1,6-anhydro-MurNAc termini of degraded PG in bacteria, we designed and synthesized Glc-NAc-1,6-anhydro-MurNAc structures with and without a pendant peptide (1-deAA) within 15 steps, and demonstrated that these compounds were utilized by bacterial TGase as non-canonical anhydro glycosyl acceptors in vitro. The incorporation of anhydro-muramyl moiety into PG strands by TGases effectively terminates of glycan chain elongation. Moreover, the preliminary in vitro studies of 1-deAA against S. aureus proved it a reasonable antimicrobial adjunct of vancomycin. For more details of the work, see: Xiao-Lin Zhang, Gábor Báti, Chenyu Li, Aoxin Guo, Claresta Yeo, Han Ding, Kumar Bhaskar Pal, Yuan Xu, Yuan Qiao*, and Xue-Wei Liu, J. Am. Chem. Soc. 2024, 146, 7400–7407
Nanyang Technological University
School of Chemistry, Chemical Engineering and Biotechnology (CCEB)